The influence of advanced maternal age on congenital malformations, short- and long-term outcomes in offspring of nulligravida: a Korean National Cohort Study over 15 years.

Objective: To assess the influence of advanced maternal age on congenital malformations, and short- and long-term outcomes in offspring of nulligravida. Methods: A retrospective study was conducted using the Korean National Health Insurance Service database spanning from January 2005 to December 2019. All live-born offspring of nulligravida (n=3,685,817) were included. The maternal age was subdivided into the following subgroups: <25 years (n=153,818), 25-29 years (n=845,355), 30-34 years (n=1,738,299), 35-39 years (n=787,530), 40-44 years (n=151,519), and >44 years (n=9,296). Outcomes were assessed based on ICD-10 codes. Adjusted odds ratios (aORs) were calculated with the group of 25-29 years as a reference using logistic regression and Cox proportional hazards model analysis. Results: Most congenital malformations showed an age-dependent increase, but cleft lip and abdominal wall defect exhibited a U-shape curve, indicating an increase even in those <25 years old. Similarly, various disorders included in the neonatal composite outcomes from short-term outcomes showed an age-dependent escalation. However, preterm birth from the short-term outcomes and most of the long-term developmental outcomes, except for motor developmental delays and Tics, showed a U-shaped pattern. The aOR of autism and cerebral palsy, showing the most obvious U-shaped curved in the long-term outcomes, was 1.50 (95% CI 1.24-1.82) and 1.54 (95% CI 1.17-2.03), respectively in the >44 years old group and 1.18 (95% confidence interval [CI], 1.11-1.25) and 1.19 (95% CI, 1.09-1.30) in the <25 years old group. Conclusion: Overall, an advanced maternal age shows an age-dependent correlation with most congenital malformations, as well as short- and long-term outcomes of neonates.

Comparison of analgesic effects between programmed intermittent epidural boluses and continuous epidural infusion after cesarean section: a randomized controlled study.

Background: This study aimed to compare the analgesic effects of programmed intermittent epidural boluses (PIEB) and continuous epidural infusion (CEI) for postoperative analgesia after elective cesarean section (CS). Methods: Seventy-four women who underwent elective CS were randomized to receive either PIEB or CEI. The PIEB group received 4 ml-intermittent boluses of 0.11% ropivacaine every hour at a rate of 120 ml/h. The CEI group received a constant rate of 4 ml/h of 0.11% ropivacaine. The primary outcome was the pain score at rest at 36 h after CS. Secondary outcomes included the pain scores during mobilization, time-weighted pain scores, the incidence of motor blockade, and complications-related epidural analgesia during 36 h after CS. Results: The pain score at rest at 36 h after CS was significantly lower in the PIEB group compared with that in the CEI group (3.0 vs. 0.0; median difference, 2; 95% CI: 1, 2; P < 0.001). The mean time-weighted pain scores at rest and during mobilizations were also significantly lower in the PIEB group than in the CEI group (pain at rest: mean differences, 37.5; 95% CI, [24.6, 50.4]; P < 0.001; pain during mobilization: mean difference, 56.6; 95% CI, [39.8, 73.5]; P < 0.001). The incidence of motor blockade was significantly reduced in the PIEB group compared with that in the CEI group (P < 0.001). Conclusion: PIEB provides superior analgesia with less motor blockade than CEI in postpartum women after CS, without any apparent adverse events.

Hydroxychloroquine in obstetrics: potential implications of the prophylactic use of hydroxychloroquine for placental insufficiency during pregnancy.

Proper placentation during early pregnancy is a key factor for maintaining a healthy pregnancy. Placental insufficiency leads to critical complications such as preeclampsia, fetal growth restriction, and fetal demise. These complications are often associated with pathological findings of restricted remodeling and obstructive lesions of the myometrial spiral arteries, which have high recurrence rates during subsequent pregnancies. Currently, there are no pharmacological interventions other than aspirin for the prevention of preeclampsia. Hydroxychloroquine (HCQ), a well-known antimalarial drug, reduces inflammatory and thrombotic changes in vessels. For decades, the use of HCQ for autoimmune diseases has resulted in the successful prevention of both arterial and venous thrombotic events and has been extended to the treatment of lupus and antiphospholipid antibody syndrome during pregnancy. HCQ reduces the risk of preeclampsia with lupus by up to 90%. Several recent studies have investigated whether HCQ improves pregnancy outcomes in women with a history of poor outcomes. In addition, in vitro and animal studies have demonstrated the beneficial effects of HCQ in improving endothelial dysfunction and alleviating hypertension and proteinuria. Therefore, we hypothesized that HCQ has the potential to attenuate the vascular inflammatory and thrombogenic pathways associated with placental insufficiency and conducted a multicenter clinical trial on the efficacy of combining aspirin with HCQ for pregnancies at high risk for preeclampsia in Korea. This study summarizes the potential effects of HCQ on pregnancies with placental insufficiency and the implications of HCQ treatment in the field of obstetrics.

Antenatal Magnesium Sulfate Is Not Associated With Improved Long-Term Neurodevelopment and Growth in Very Low Birth Weight Infants.

BACKGROUND: Though antenatal magnesium sulfate (MgSO4) is widely used for fetal neuroprotection, suspicions about the long-term neuroprotection of antenatal MgSO4 have been raised. METHODS: We investigated short- and long-term outcomes of antenatal MgSO4 use for 468 infants weighing < 1,500 g with a gestational age of 24-31 weeks. RESULTS: Short-term morbidities and the risk of developmental delay, hearing loss, and cerebral palsy at a corrected age of 18-24 months and 3 years of age did not decrease in the MgSO4 group (infants who were exposed to MgSO4 for any purpose) or neuroprotection group (infants who were exposed to MgSO4 for fetal neuroprotection) compared with the control group (infants who were not exposed to MgSO4). The z-scores of weight, height, and head circumference did not increase in the MgSO4 group or neuroprotection group compared with the control group. CONCLUSION: Antenatal MgSO4 including MgSO4 for neuroprotection did not have beneficial effects on long-term neurodevelopmental and growth outcomes.

Effect of delayed cord clamping on maternal and neonatal outcome in twin pregnancies: a retrospective cohort study.

The objective of this study was to compare the maternal and neonatal outcomes following delayed cord clamping (DCC) versus immediate cord clamping (ICC) in twin pregnancies. This was a retrospective cohort study of 705 twin pregnancies who delivered at ≥ 24 weeks of gestation. Maternal and neonatal hemoglobin levels, blood transfusion, and neonatal outcomes were compared between DCC (n = 225) and ICC (n = 480) groups. Mean maternal predelivery and postpartum hemoglobin levels and the rate of postpartum hemoglobin drop ≥ 20% or maternal blood transfusion were comparable between the two groups. The DCC group had a significantly higher mean neonatal hemoglobin level (DCC vs. ICC: 17.4 ± 3.5 vs. 16.6 ± 2.7 g/dl, P = 0.010) but significantly lower rates of neonatal blood transfusion (DCC vs. ICC: 3.3% vs. 8.8%, P < 0.001) and respiratory distress syndrome (DCC vs. ICC: 6.7% vs. 15.2%, P < 0.001) than the ICC group. In conclusion, DCC compared with ICC in twin pregnancy was not associated with an increase of maternal postpartum bleeding complications, but it was associated with higher neonatal hemoglobin level and lower risks of neonatal blood transfusion and respiratory distress syndrome.

Obesity Is Associated With Higher Risk of Adverse Maternal and Neonatal Outcomes Than Supervised Gestational Diabetes.

BACKGROUND: Unlike gestational diabetic mellitus (GDM), which is strictly managed by most patients and physicians, obesity does not have proper management guidelines, and the importance of its management during pregnancy is often ignored. The aim of this study was to compare maternal and neonatal outcomes according to obesity and GDM, alone or in combination. METHODS: This was a retrospective cohort study of 3,078 consecutive pregnant women who experienced prenatal care and delivery of a live singleton neonate between January 2016 and December 2020 at our institution. Study participants were categorized into 4 mutually exclusive groups, as follows: group 1, no GDM without obesity; group 2, GDM without obesity; group 3, no GDM with obesity; and group 4, GDM with obesity. RESULTS: Compared to group 2, group 3 had higher rates of pre-eclampsia, cesarean section including emergent cesarean section rate. Also, neonates in group 3 were heavier and had lower glucose levels compared to those in group 2. Of note, there was no significant difference in maternal or neonatal outcomes except the rate of large-for-gestational-age (LGA) between group 1 and group 2. Among the GDM groups, group 4 had higher risks for pre-eclampsia, cesarean section, and LGA infant status than group 2. CONCLUSION: Our data showed that obese women without GDM face higher risk of adverse pregnancy outcomes than women with supervised GDM and non-obese women. We also confirmed that adverse pregnancy outcomes associated with GDM were mainly attributable to obesity among women receiving GDM education.

The Multifaceted Clinical Characteristics of Congenital Cytomegalovirus Infection: From Pregnancy to Long-Term Outcomes.

BACKGROUND: The aim of this study was to capture multifaceted clinical characteristics of congenital cytomegalovirus (CMV) infection from diagnosis to treatment using a multidisciplinary approach including obstetrics, pediatrics, pathology, and otorhinolaryngology-head and neck surgery. METHODS: This is a retrospective study including 30 consecutive cases of congenital CMV infection that were diagnosed at a single tertiary hospital located in Seoul, Korea from January 2009 to December 2020. Congenital CMV infection was defined as a positive result by polymerase chain reaction from urine, saliva or cerebrospinal fluid or positive CMV IgM from neonatal blood sampled within 3 weeks after birth. All cases were analyzed with respect to whole clinical characteristics from diagnosis to treatment of congenital CMV by a multidisciplinary approach including prenatal sonographic findings, maternal immune status regarding CMV infection, detailed placental pathology, neonatal clinical manifestation, auditory brainstem response test, and antiviral treatment (ganciclovir or valganciclovir). Long-term outcomes including developmental delay and hearing loss were also investigated. RESULTS: The total number of births during the study period in our institution was 19,385, with the prevalence of congenital infection estimated to be 0.15%. Among 30 cases of congenital CMV, the median gestational age at delivery was 32.2 weeks [range, 22.6-40.0] and 66.7% of these infants were delivered preterm at less than 37 weeks. Suspected fetal growth restriction was the most common prenatal ultrasound finding (50%) followed by ventriculomegaly (17.9%) and abnormal placenta (17.9%), defined as thick placenta with calcification. No abnormal findings on ultrasound examination were observed in one-third of births. Maternal CMV serology tests were conducted in only 8 cases, and one case each of positive and equivocal IgM were found. The most common placental pathologic findings were chronic villitis (66.7%) and calcification (63.0%), whereas viral inclusions were identified in only 22.2%. The most common neonatal manifestations were jaundice (58.6%) followed by elevation of aspartate aminotransferase (55.2%) and thrombocytopenia (51.7%). After excluding cases for which long-term outcomes were unavailable due to death (n = 4) or subsequent follow up loss (n = 3), developmental delay was confirmed in 43.5% of infants (10/23), and hearing loss was confirmed in 42.9% (9/21) during the follow-up period. In our cohort, 56.7% (17/30) of neonates were treated for congenital CMV with ganciclovir or valganciclovir. CONCLUSION: Our data show that prenatal findings including maternal serologic tests and ultrasound have limited ability to detect congenital CMV in Korea. Given that CMV is associated with high rates of developmental delay and hearing loss in infants, there is an urgent need to develop specific strategies for the definite diagnosis of congenital CMV infection during the perinatal period by a multidisciplinary approach to decrease the risks of neurologic impairment and hearing loss through early antiviral treatment.

Mesenchymal Stem Cell-Extracellular Vesicle Therapy for Stroke: Scalable Production and Imaging Biomarker Studies.

A major clinical hurdle to translate MSC-derived extracellular vesicles (EVs) is the lack of a method to scale-up the production of EVs with customized therapeutic properties. In this study, we tested whether EV production by a scalable 3D-bioprocessing method is feasible and improves neuroplasticity in animal models of stroke using MRI study. MSCs were cultured in a 3D-spheroid using a micro-patterned well. The EVs were isolated with filter and tangential flow filtration and characterized using electron microscopy, nanoparticle tracking analysis, and small RNA sequencing. Compared to conventional 2D culture, the production-reproduction of EVs (the number/size of particles and EV purity) obtained from 3D platform were more consistent among different lots from the same donor and among different donors. Several microRNAs with molecular functions associated with neurogenesis were upregulated in EVs obtained from 3D platform. EVs induced both neurogenesis and neuritogenesis via microRNAs (especially, miR-27a-3p and miR-132-3p)-mediated actions. EV therapy improved functional recovery on behavioral tests and reduced infarct volume on MRI in stroke models. The dose of MSC-EVs of 1/30 cell dose had similar therapeutic effects. In addition, the EV group had better anatomical and functional connectivity on diffusion tensor imaging and resting-state functional MRI in a mouse stroke model. This study shows that clinical-scale MSC-EV therapeutics are feasible, cost-effective, and improve functional recovery following experimental stroke, with a likely contribution from enhanced neurogenesis and neuroplasticity.

Abnormal Vaginal Flora in Cervical Incompetence Patients - the Impact of Escherichia coli.

The purpose of this study was to investigate the prevalence of abnormal vaginal colonization in women with cervical incompetence and to analyze its impact on obstetric and neonatal outcomes and placental inflammation. We included 138 pregnant women diagnosed with cervical incompetence and delivered in our hospital. Patients with major fetal anomaly or multifetal pregnancy were excluded. Upper vaginal culture was performed on the day of admission. A total of 60.9% (84/138) of cervical incompetence patients had abnormal bacterial colonization, and Escherichia coli (E. coli) was the most common colonized pathogen (33.3%, 46/138). The positive vaginal E. coli group had a higher rate of prior preterm birth (p = 0.021) and an earlier gestational age at which cervical incompetence was diagnosed (p < 0.01) than the negative group. The positive vaginal E. coli group had higher rates of clinical chorioamnionitis (p = 0.008) and subchorionic microabscess of the placenta (p = 0.012). Importantly, the positive vaginal E. coli group had significantly higher rates of proven early-onset neonatal sepsis (EONS) (p = 0.046), necrotizing enterocolitis (NEC) (p = 0.001), and neonatal mortality (p = 0.023). After adjusting for confounding variables, the positive vaginal E. coli group had significantly higher risk for proven EONS (OR: 3.853, 95% CI: 1.056-14.055) and NEC (OR: 12.410, 95% CI: 1.290-119.351). In conclusion, E. coli was the most common vaginal microorganism isolated from patients with cervical incompetence. Maternal vaginal E. coli colonization was associated with adverse neonatal outcomes including proven EONS and NEC and was characterized by a higher rate of placental subchorionic microabscess.

Clinical-Scale Mesenchymal Stem Cell-Derived Extracellular Vesicle Therapy for Wound Healing.

We developed an extracellular vesicle (EV) bioprocessing platform for the scalable production of human Wharton's jelly mesenchymal stem cell (MSC)-derived EVs. The effects of clinical-scale MSC-EV products on wound healing were tested in two different wound models: subcutaneous injection of EVs in a conventional full-thickness rat model and topical application of EVs using a sterile re-absorbable gelatin sponge in the chamber mouse model that was developed to prevent the contraction of wound areas. In vivo efficacy tests showed that treatment with MSC-EVs improved the recovery following wound injury, regardless of the type of wound model or mode of treatment. In vitro mechanistic studies using multiple cell lines involved in wound healing showed that EV therapy contributed to all stages of wound healing, such as anti-inflammation and proliferation/migration of keratinocytes, fibroblasts, and endothelial cells, to enhance wound re-epithelialization, extracellular matrix remodeling, and angiogenesis.

Neonatal and maternal adverse outcomes and exposure to nonsteroidal anti-inflammatory drugs during early pregnancy in South Korea: A nationwide cohort study.

BACKGROUND: Existing data on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) during late pregnancy is well established, providing assurance. However, the use of NSAIDs during early pregnancy remains inconclusive owing to conflicting findings on adverse neonatal outcomes as well as the limited data on adverse maternal outcomes. Therefore, we sought to investigate whether early prenatal exposure to NSAIDs was associated with neonatal and maternal adverse outcomes. METHODS AND FINDINGS: We conducted a nationwide, population-based cohort study using Korea's National Health Insurance Service (NHIS) database with a mother-offspring cohort constructed and validated by the NHIS to include all live births in women aged 18 to 44 years between 2010 and 2018. We defined exposure to NSAIDs as at least two records of NSAID prescriptions during early pregnancy (first 90 days of pregnancy for congenital malformations and first 19 weeks for nonmalformation outcomes) and compared against three distinct referent groups of (1) unexposed, no NSAID prescription during the 3 months before pregnancy start to end of early pregnancy; (2) acetaminophen-exposed, at least two acetaminophen prescriptions during early pregnancy (i.e., active comparator); and (3) past users, at least two NSAID prescriptions before the start of pregnancy but no relevant prescriptions during pregnancy. Outcomes of interest were adverse birth outcomes of major congenital malformations and low birth weight and adverse maternal outcomes of antepartum hemorrhage and oligohydramnios. We estimated relative risks (RRs) with 95% CIs using generalized linear models within a propensity score (PS) fine stratification weighted cohort that accounted for various potential confounders of maternal sociodemographic characteristics, comorbidities, co-medication use, and general markers of burden of illness. Of 1.8 million pregnancies in the PS weighted analyses, exposure to NSAIDs during early pregnancy was associated with slightly increased risks for neonatal outcomes of major congenital malformations (PS-adjusted RR, 1.14 [CI, 1.10 to 1.18]) and low birth weight (1.29 [1.25 to 1.33]), and for maternal outcome of oligohydramnios (1.09 [1.01 to 1.19]) but not antepartum hemorrhage (1.05 [0.99 to 1.12]). The risks of overall congenital malformations, low birth weight, and oligohydramnios remained significantly elevated despite comparing NSAIDs against acetaminophen or past users. Risks of adverse neonatal and maternal outcomes were higher with cyclooxygenase-2 selective inhibitors or use of NSAIDs for more than 10 days, whereas generally similar effects were observed across the three most frequently used individual NSAIDs. Point estimates were largely consistent across all sensitivity analyses, including the sibling-matched analysis. Main limitations of this study are residual confounding by indication and from unmeasured factors. CONCLUSIONS: This large-scale, nationwide cohort study found that exposure to NSAIDs during early pregnancy was associated with slightly higher risks of neonatal and maternal adverse outcomes. Clinicians should therefore carefully weigh the benefits of prescribing NSAIDs in early pregnancy against its modest, but possible, risk of neonatal and maternal outcomes, where if possible, consider prescribing nonselective NSAIDs for <10 days, along with continued careful monitoring for any safety signals.

A randomized clinical trial of antibiotic treatment duration in preterm pre-labor rupture of membranes: 7 days vs until delivery.

BACKGROUND: Antibiotic treatment in preterm pre-labor rupture of membranes can prolong the interval from membrane rupture to delivery and improve neonatal outcomes. However, the duration of antibiotic treatment for preterm pre-labor rupture of membranes has been rarely compared in prospective studies. OBJECTIVE: This study aimed to investigate the optimal duration of antibiotic treatment for pre-labor rupture of membranes. We performed a randomized controlled trial comparing neonatal morbidity and infantile neurologic outcomes between 2 groups of patients with preterm pre-labor rupture of membranes who received antibiotic treatment for 7 days or until delivery, respectively. STUDY DESIGN: This prospective randomized study included patients who were diagnosed with preterm pre-labor rupture of membranes between 22+0 weeks and 33+6 weeks of gestation. The enrolled patients were randomly assigned to receive intravenous cefazolin (1 g dosage every 12 hours) and oral clarithromycin (500 mg dosage every 12 hours) either for 7 days or until delivery. The study protocol was registered at ClinicalTrials.gov under identifier NCT01503606. The primary outcome was a neonatal composite morbidity, and the secondary outcome was neurologic outcomes at 12 months of corrected age. We enrolled 151 patients and allocated 75 and 76 of them to the 7-day and until-delivery groups, respectively. Analysis was done by per protocol. RESULTS: After excluding cases lost to follow-up and those with protocol violations, 63 (7-day regimen) and 61 (until-delivery regimen) patients with preterm pre-labor rupture of membranes and their babies were compared. There was no significant difference in the pregnancy outcomes, including gestational age at delivery and the interval from rupture of membranes to delivery, between the 2 groups. Among the neonatal outcomes, bronchopulmonary dysplasia, intraventricular hemorrhage, retinopathy of prematurity, necrotizing enterocolitis, and proven neonatal sepsis did not differ between the groups. However, the rates of respiratory distress syndrome (32.8% vs 50.8%; P=.039) and composite neonatal morbidities (34.4% vs 53.9%; P=.026) were lower in the until-delivery group than in the 7-day group. This difference remained statistically significant after a multivariable analysis adjusting for maternal age, twin pregnancy, antenatal corticosteroids treatment, gestational age at delivery, interval from rupture of membranes to delivery, and clinical chorioamnionitis. Infantile neurologic outcomes were evaluated in 71.4% of the babies discharged alive and did not differ between the groups. CONCLUSION: Overall, the until-delivery regimen of cefazolin and clarithromycin in preterm pre-labor rupture of membranes led to a lower incidence of composite neonatal morbidity and respiratory distress syndrome than the 7-day regimen, and both regimens otherwise showed similar individual neonatal morbidities and infantile neurologic outcomes.

The Skin Antiseptic agents at Vaginal dElivery (SAVE) trial: study protocol for a randomized controlled trial.

BACKGROUND: Cleansing of the vulva and perineum is recommended during preparation for vaginal delivery, and special attention is paid to cleansing before episiotomy because episiotomy is known to increase the risk of perineal wound infection and/or dehiscence. However, the optimal method of perineal cleansing has not been established, including the choice of antiseptic agent. To address this issue, we designed a randomized controlled trial to examine whether skin preparation with chlorhexidine-alcohol is superior to povidone-iodine for the prevention of perineal wound infection after vaginal delivery. METHODS: In this multicenter randomized controlled trial, term pregnant women who plan to deliver vaginally after episiotomy will be enrolled. The participants will be randomly assigned to use antiseptic agents for perineal cleansing (povidone-iodine or chlorhexidine-alcohol). The primary outcome is superficial or deep perineal wound infection within 30 days after vaginal delivery. The secondary outcomes are the length of hospital stay, physician office visits, or hospital readmission for infection-related complications, endometritis, skin irritations, and allergic reactions. DISCUSSION: This study will be the first randomized controlled trial aiming to determine the optimal antiseptic agent for the prevention of perineal wound infections after vaginal delivery. TRIAL REGISTRATION: ClinicalTrials.gov NCT05122169. First submitted date on 8 November 2021. First posted date on 16 November 2021.

Growing threat of extended-spectrum ß-lactamase-producing Enterobacteriaceae colonisation in high-risk pregnancies: A cross-sectional study.

OBJECTIVE: To investigate the epidemiological changes in extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-E) vaginal colonisation in pregnant women deemed at high risk, and to identify independent risk factors. Further, the differences in perinatal outcomes according to maternal ESBL-E vaginal colonisation were analysed. DESIGN: Cross-sectional study. SETTING: Republic of Korea. POPULATION: A cohort of 1460 women admitted to our high-risk pregnancy unit between 14+0 and 36+6  weeks of gestation. METHODS: The trend of changes in the association of ESBL-E vaginal colonisation from January 2010 to December 2020 was analysed. The main outcomes were analysed over the study period and ESBL-E vaginal colonisation. MAIN OUTCOME MEASURES: Rate of ESBL-E vaginal colonisation, risk factors for ESBL-E vaginal colonisation and perinatal outcomes. RESULTS: The ESBL-E vaginal colonisation rate has tended to increase over the past 11 years, which was attributed to a significantly higher proportion of ESBL-producing Escherichia coli. Cerclage (RR 3.7, 95% CI 2.19-6.40) and prior antibiotic treatment (RR 4.0, 95% CI 2.44-6.54) were found as independent risk factors for ESBL-E vaginal colonisation. Earlier gestational age at delivery and higher proven early-onset neonatal sepsis (EONS) rate were observed in the ESBL-E-positive group. CONCLUSIONS: The ESBL-E vaginal colonisation rate in pregnant patients at high risk has increased over the past decade, and the independent risk factors for colonisation are cerclage and prior antibiotic treatment. Additionally, maternal ESBL-E vaginal colonisation is associated with higher rates of proven EONS.

Hydroxychloroquine reduces hypertension and soluble fms-like kinase-1 in a Nω-nitro-l-arginine methyl ester-induced preeclampsia rat model.

OBJECTIVE: Hydroxychloroquine, a drug used for malaria and autoimmune diseases reportedly has beneficial effects against preeclampsia in pregnant women with lupus. However, its mechanism against preeclampsia remains unclear. We investigated the effect of hydroxychloroquine on an Nω-nitro-l-arginine methyl ester-induced preeclampsia rat model. METHODS: Pregnant Sprague-Dawley rats were divided into four groups based on treatment (administered on gestational days 7-18): control, Nω-nitro-l-arginine methyl ester, hydroxychloroquine, and Nω-nitro-l-arginine methyl ester plus hydroxychloroquine. All animals were sacrificed on gestational day 19. We assayed tube formation and determined reactive oxygen species levels using human umbilical vein endothelial cells. RESULTS: Results showed that hydroxychloroquine significantly lowered mean systolic blood pressure (P  < 0.05) in Nω-nitro-l-arginine methyl ester-treated rats. Hydroxychloroquine did not affect their fetal and placental weights. Hydroxychloroquine mitigated Nω-nitro-l-arginine methyl ester-associated changes in proteinuria (P  < 0.05). It normalized plasma soluble fms-like kinase-1 (P  < 0.05) and endothelin-1 (P  < 0.01) levels. In the tube formation assay, hydroxychloroquine increased the total meshes area (P  < 0.05) and mitigated Nω-nitro-l-arginine methyl ester-induced reactive oxygen species formation (P  < 0.05) in human umbilical vein endothelial cells. CONCLUSION: We conclude that hydroxychloroquine alleviated hypertension, proteinuria, and normalized soluble fms-like kinase-1 and endothelin-1 levels in our preeclampsia model and that these changes may involve the restoration of endothelial dysfunction; thus, hydroxychloroquine could potentially be used for preventing preeclampsia, even in the absence of lupus.

Effect of hydroxychloroquine and chloroquine on syncytial differentiation and autophagy in primary human trophoblasts.

During placentation, cytotrophoblasts differentiate and fuse to form multinucleated cells (syncytiotrophoblasts) in a process that involves autophagy. Appropriate syncytial differentiation is essential for establishing a healthy pregnancy. In this study, we evaluated the effect of two chloroquine compounds, hydroxychloroquine (HCQ) and chloroquine (CQ), on syncytial differentiation and autophagy in cultured primary human trophoblasts (PHTs). PHT cells were isolated from the human term placenta. Bafilomycin, a well-known autophagy inhibitor, was used as a positive control. Biochemical and morphological differentiation was assessed in syncytiotrophoblasts, and autophagy-related proteins and genes were evaluated. Affymetrix Human Gene 2.0 ST Array profiling was used to identify genes affected by HCQ during syncytial differentiation. Chloroquine compounds lowered the production of beta-human chorionic gonadotropin (ß-hCG) and the fusion index in PHTs. Syncytial differentiation in PHT was associated with the increased expression of ATG4C mRNA (autophagy-related gene), and this expression was affected by CQ but not by HCQ. Microarray analysis revealed that HCQ or CQ affected several genes (MMP15, GPC3, CXCL10, TET-1, and S100A7) during syncytial differentiation, which were different from that of the syncytial differentiation suppression (Ham's/Waymouth media) or autophagy inhibition (bafilomycin treatment). Using Kyoto Encyclopedia of Genes and Genomes analysis we identified that HCQ might affect JAK2 signaling in the syncytial differentiation of PHT. In conclusion, chloroquine compounds could mitigate biochemical and morphological syncytial trophoblast differentiation in cultured PHT cells through the JAK signaling pathway rather than the inhibition of autophagic activity.

Do the Causes of Spontaneous Preterm Delivery Affect Placental Inflammatory Pathology and Neonatal Outcomes?

Objective: To investigate the severity of histologic chorioamnionitis /funisitis according to the indication for preterm delivery and their corresponding neonatal outcomes. Method: This study included 411 singleton women who delivered between 21+0 and 31+6 week of gestation due to preterm labor (PTL, n = 165), preterm premature rupture of membranes (PPROM, n = 202), or incompetent internal os of the cervix (IIOC, n = 44). The primary outcome measure was the rate of severe histological chorioamnionitis/funisitis. Secondary outcome measure was neonatal outcomes including neonatal and infant death, and neonatal composite morbidity. Results: The PPROM group demonstrated a higher rate of severe histological chorioamnionitis/funisitis compared to the PTL group (severe histological chorioamnionitis; PPROM, 66.3% vs. PTL, 49.1%, p = 0.001, severe funisitis; PPROM, 44.1% vs. PTL, 23.6%, p < 0.001) and this remained significant after multivariable analysis (severe histologic chorioamnionitis, OR 2.367, 95% CI 1.517−3.693; severe funisitis, OR 2.668, 95% CI 1.684−4.226). For neonatal outcomes only, a higher rate of patent ductus arteriosus was observed in the IIOC group compared to the PTL and PPROM groups (IIOC, 77.3% vs. PTL, 54.0% vs. PPROM, 54.0%, p = 0.043) and this remained significant after multivariable analysis. Conclusion: Indication of spontaneous preterm delivery might affect the placental inflammatory pathology and neonatal morbidity.

Mitochondrial energy metabolic transcriptome profiles during cardiac differentiation from mouse and human pluripotent stem cells.

Simultaneous myofibril and mitochondrial development is crucial for the cardiac differentiation of pluripotent stem cells (PSCs). Specifically, mitochondrial energy metabolism (MEM) development in cardiomyocytes is essential for the beating function. Although previous studies have reported that MEM is correlated with cardiac differentiation, the process and timing of MEM regulation for cardiac differentiation remain poorly understood. Here, we performed transcriptome analysis of cells at specific stages of cardiac differentiation from mouse embryonic stem cells (mESCs) and human induced PSCs (hiPSCs). We selected MEM genes strongly upregulated at cardiac lineage commitment and in a time-dependent manner during cardiac maturation and identified the protein-protein interaction networks. Notably, MEM proteins were found to interact closely with cardiac maturation-related proteins rather than with cardiac lineage commitment-related proteins. Furthermore, MEM proteins were found to primarily interact with cardiac muscle contractile proteins rather than with cardiac transcription factors. We identified several candidate MEM regulatory genes involved in cardiac lineage commitment (Cck, Bdnf, Fabp4, Cebpα, and Cdkn2a in mESC-derived cells, and CCK and NOS3 in hiPSC-derived cells) and cardiac maturation (Ppargc1α, Pgam2, Cox6a2, and Fabp3 in mESC-derived cells, and PGAM2 and SLC25A4 in hiPSC-derived cells). Therefore, our findings show the importance of MEM in cardiac maturation.

Diagnostic Accuracy of Loop-Mediated Isothermal Amplification Assay for Group B Streptococcus Detection in Recto-Vaginal Swab: Comparison with Polymerase Chain Reaction Test and Conventional Culture.

A rapid method for obtaining group B streptococcus (GBS) screening results has been required in the obstetric field. We aimed to determine the diagnostic performance of the Loop-Mediated Isothermal Amplification (LAMP) assay is acceptable compared to the existing polymerase chain reaction (PCR) assay. The study involved 527 pregnant women aged 19 to 44 years. Rectovaginal swabs were collected between 35 and 37 weeks of gestation or prior to impending preterm births or term labor without GBS screening. We presented the diagnostic performance of the LAMP assay with a 95% confidence interval (CI) compared to the PCR and microbiological culture. In total, 115 (21.8%), 115 (21.8%) and 23 (4.4%) patients showed positive results using the LAMP, PCR assay and microbiological culture method, respectively. The LAMP assay showed 100% sensitivity (95% CI, 96.8-100.0), 100% specificity (95% CI, 99.1-100.0) and 100% diagnostic accuracy (95% CI, 99.3-100.0) with the reference being the PCR assay. Meanwhile, the LAMP assay showed 87.0% sensitivity (95% CI, 71.0-100.0), 81.2% specificity (95% CI, 77.6-84.7), and 81.4% diagnostic accuracy (95% CI, 78.0-84.8) with the microbiological culture as a reference. This study presented the LAMP assay as an acceptable method for GBS screening with a similar performance to the existing PCR method.